It is a problem to accurately detect the presence of and determine the locus of invasive agents, such as pathogens and cancers (malignant neoplasm), (collectively termed “invasive agents” herein) in a living organism (ex.—human, animal). Most invasive agents are initially recognized either because signs or symptoms appear in the living organism that is infected with the invasive agents or through screening tests which commonly include blood tests, X-rays, CT scans, MRI and endoscopy, for example. None of these processes leads to a definitive diagnosis, which usually requires the opinion of a pathologist who specializes in the diagnosis of invasive agents and other diseases. However, even with expert analysis, the diagnosis is still somewhat subjective in nature.
Presently, a procedure is being used where nano-particles are directed to invasive cells (cancer cells) by the use of passive and active targeting methods. The passive targeting approach uses the size and shape of the nano-particles to enhance their uptake into cancer cells while the active targeting approach uses coatings applied to the nano-particles (such as an antigen) to enable the targeted uptake of the nano-particles by only those cells, cancer cells for instance, that are susceptible to the antigen coating. Other coating methods using other materials are presently being studied by those in the art to facilitate nano-particle uptake in cancer cells.
Now that nano-particles can be inserted into the living organism through intravenous application as well as direct injection of particles at the cancerous site, and uniquely directed to specific cancer cells via either active or passive targeting, an opportunity exists for enhanced imaging of cancerous lesions. Conceptually, since many thousands of nano-particles can fit into a cancer cell, non-lumpy cancers could be “imaged” or detected. This is a function of using the correct frequencies and energy levels to enable imaging at the desired size or scale resolution. In concept then, mammograms for breast cancer imaging, which have size resolution detections in the tens of millimeters range, would be clearly eclipsed by the approaches described herein which can conceptually image at the cellular level.
Recent laboratory techniques have been explored using nano-particles as a contrast agent, seeking to improve both the imaged Signal-to-Noise ratio as well as the differentiation between cancerous tissue and healthy tissue, provided that the nano-particles were targeted to the cancer cells. Some of these published techniques have discussed using the notion of micro-bubbles, thereby creating an air dielectric region. This technique is easily replicated in the lab but does not readily translate to the in vivo live human environment. Other techniques have used iron ferrite particles, but with limited contrast improvement. What is needed is a nano-particle/field pairing that optimizes the “output energy” response of the nano-particles to enable enhanced imaging over what is accomplished in today's art.
One such possible imaging method involves the use of an acoustic imaging system. Tissue responds to an energy pulse, whether it is RF or microwave or laser, by expanding under the influence of the energy pulse, and then contracting. During such physical changes, albeit extremely slight, the tissue emits an acoustical signature that is unique to its material composition. Similarly, a specially designed particle that responds, preferably dramatically, to the EM or laser energy pulse, would create a significant and correlated acoustic response. This is one method of enhanced imaging detection, by using nano-particles that are specially designed to emit an enhanced acoustical signature when illuminated, where the acoustical signature is unique to the nano-particle and different from the surrounding tissue response.
Alternatively, a second possible imaging method involves directly using the material properties of the nano-particles to enhance imaging contrast. Nano-particles can be designed and made in significant volume with consistent material properties which are unique and novel compared to normal tissue, say breast tissue. However, the efforts to date using nano-particle material properties have involved using traditional MRI contrast agents but in a non-MRI environment. Again, this is non-optimal and results in a method that does not fully exploit the notion of pairing nano-particle with field types to maximize imaging capabilities. If the illuminating field types were matched to the material properties of the nano-particle, the nano-particle can be detected by the very nature of their material properties, where the properties are uniquely different from that of normal tissue, and an advance would be made that is unique and novel over the existing art.
Using cancer as an example, there are presently several common approaches to treating cancer, once it is detected: surgical, chemotherapy, radiation therapy, immunotherapy, and monoclonal antibody therapy, all of which have severe negative effects on the living organism. A significant problem with this paradigm is that the diagnosis and treatment of invasive agents are radically different processes with limited linkage between the two.
The surgical approach to cancer treatment is the traditional process where a surgeon makes an incision into the living organism and manually attempts to excise the cancerous tissue. A problem with this approach is that it is invasive, stressful to the living organism, and difficult to precisely excise only the cancerous tissue and not remove healthy tissue from the site of the cancer. While removal of small amounts of healthy tissue is typically not problematic, it is difficult to excise all the cancerous tissue, with minimal healthy tissue and not leave behind any cancerous tissue. Therefore the typical surgical practice is to remove a “reasonable” amount of surrounding healthy tissue, since the downside of missing cancerous cells is unacceptable recurrence of the cancer. The surgical approach is therefore traumatic and imprecise.
Chemotherapy is the use of toxic chemicals (drugs) to kill the cancer cells. This procedure typically results in severe side effects since the chemotherapy drugs also negatively impact the living organism, killing healthy cells, injuring the vital organs in the process of destroying the cancerous cells. A long regimen of chemotherapy is required to cleanse the living organism of the cancer cells and in many cases a combination of drugs is used to ensure that the cancer cells are destroyed. Most commonly, chemotherapy acts by killing cells that divide rapidly, one of the main properties of most cancer cells. This means that it also harms cells that divide rapidly under normal circumstances: cells in the bone marrow, digestive tract and hair follicles; this results in the most common side effects of chemotherapy—myelosuppression (decreased production of blood cells), mucositis (inflammation of the lining of the digestive tract) and alopecia (hair loss). Newer anticancer drugs act directly against abnormal proteins in cancer cells; this is termed targeted therapy. An additional problem with chemotherapy is that the cancer cells adapt to the treatment, developing immunity to the drugs that are administered, thereby requiring a sequence of different drugs to provide an effective treatment.
Radiation Therapy is the use of radiation to kill the cancer cells. This procedure typically results in severe side effects since the radiation also negatively impacts the living organism, killing healthy cells as well as the cancerous cells. A long regimen of radiation therapy is required to cleanse the living organism of the cancer to ensure that the cancer cells are destroyed. Radiation therapy is the medical use of ionizing radiation as part of cancer treatment to control malignant cells and may be used for curative or adjuvant treatment. It is also used as palliative treatment (where cure is not possible and the aim is for local disease control or symptomatic relief) or as therapeutic treatment (where the therapy has survival benefit and it can be curative). It is also common to combine radiotherapy with surgery, chemotherapy, hormone therapy or some mixture of the three. Most common cancer types can be treated with radiation therapy in some way. The precise treatment intent (curative, adjuvant, neoadjuvant, therapeutic, or palliative) depends on the tumor type, location, and stage, as well as the general health of the subject.
Radiation therapy is commonly applied to the cancerous tumor. The radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with tumor, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumor to allow for uncertainties in daily set-up and internal tumor motion. These uncertainties can be caused by internal movement (for example, respiration and bladder filling) and movement of external skin marks relative to the tumor position. To spare normal tissues (such as skin or organs which radiation must pass through in order to treat the tumor), shaped radiation beams are aimed from several angles of exposure to intersect at the tumor, providing a much larger absorbed dose there than in the surrounding, healthy tissue. Radiation therapy works by damaging the DNA of cells. The damage is caused by a photon, electron, proton, neutron, or ion beam directly or indirectly ionizing the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA. In the most common forms of radiation therapy, most of the radiation effect is through free radicals. Because cells have mechanisms for repairing DNA damage, breaking the DNA on both strands proves to be the most significant technique in modifying cell characteristics. Because cancer cells generally are undifferentiated and stem cell-like, they reproduce more, and have a diminished ability to repair sub-lethal damage compared to most healthy differentiated cells. The DNA damage is inherited through cell division, accumulating damage to the cancer cells, causing them to die or reproduce more slowly.
Cancer immunotherapy attempts to stimulate the immune system to reject and destroy tumors. In the beginning immunotherapy treatments involved administration of cytokines such as Interleukin with an aim of inducing the lymphocytes to carry on their activity of destroying the tumor cells. Thereafter the adverse effects of such intravenously administered cytokines lead to the extraction of the lymphocytes from the blood and culture-expanding them in the lab and then injecting the cells alone to enable them to destroy the cancer cells.
Monoclonal antibody therapy is the use of monoclonal antibodies (or mAb) to specifically bind to target cells. This may then stimulate the patient's immune system to attack those cells. It is possible to create a monoclonal antibodies specific to almost any extracellular/cell surface target, and thus there is a large amount of research and development to create monoclonal antibodies for numerous serious diseases (such as rheumatoid arthritis, multiple sclerosis and different types of cancers). There are a number of ways that monoclonal antibodies can be used for therapy. For example: monoclonal antibodies therapy can be used to destroy malignant tumor cells and prevent tumor growth by blocking specific cell receptors.
A new, relatively imprecise approach to diagnose cancer is the injection of nano-particles into the living organism and the subsequent activation of the nano-particles via the use of a magnetic field. The size of the nano-particles is selected to enable the cancer cells to ingest the nano-particles, yet not be able to excrete the ingested nano-particles. In addition, the nano-particles can be coated with a substance to make the nano-particles more susceptible to ingestion by the cancer cells, or more likely to bind to the cell surface of the cancer cells. The nano-particles can be heated to raise the temperature of the cancer cells, thereby killing the cancer cells, or the nano-particles can be formed to encapsulate cancer-killing drugs, which are released into the cancer cell by the application of the magnetic field. However, this process is in the early stages of development and has yet to reach a level of maturity where the physical processes and their limitations are well understood.
Thus, there presently is no procedure that can be used to accurately detect the presence of cancer cells in a living organism or treat the cancer cells, once detected, to destroy the cancer cells, without serious negative effects on the living organism. Present diagnostic and treatment procedures are macro and non-specific in their approach and result in damage to the living organism in order to destroy the cancer cells. Additionally, the cost of present day imaging methods, such as an MRI or CT scan, is prohibitive for annual screening check-ups and is reserved for only the most serious of cases. Routine mammograms, specialized x-rays of the human breast, offer limited contrast as well as limited resolution. Mammogram resolution is only to the tens of millimeters range, and some mammograms cannot detect physical masses less than five millimeters. In addition, mammograms have a very high false positive rate, meaning subsequent additional tests are necessary just to “make sure”. Worse yet, mammograms often fail to find true cancerous lesions. Certain tissue types, such as fibrous breasts, common in older women, and breast implants made of saline and other materials, further complicate the accuracy of mammograms. Finally, mammograms use an ionizing method of imaging that over time is additive and harmful to healthy tissue. What is needed is a low cost, ubiquitous, non-ionizing imaging method wherein breast imaging enhancement can be realized via the unique pairing of non-ionizing illuminating fields with nano-particles of specific material properties, where the nano-particle response, in the given illuminating field, enables an enhanced signal to noise ratio and higher contrast than current imaging methods.